ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.84C>A (p.Ser28Arg) (rs539699299)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169378 SCV000220764 likely pathogenic Pendred syndrome 2014-10-02 criteria provided, single submitter literature only
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000505875 SCV000605155 pathogenic not provided 2017-05-19 criteria provided, single submitter clinical testing The c.84C>A variant (rs539699299) has been observed as a homozygote (Park 2003) or in trans with a pathogenic variant (Ladsous 2014) in patients with a clinical diagnosis of Pendred syndrome (PS). It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.003% (identified in 1 out of 30,956 chromosomes). Additionally, a different nucleic acid change leading to the same amino acid substitution (c.82A>C; p.Ser28Arg) a different variant in same codon (c.82A>G; p.Ser28Gly) have also been identified in patients with enlarged vestibular aqueduct (EVA; Park 2005 and Okamoto 2014, respectively). Analysis of the p.Ser28Arg variant in heterologous cell culture has revealed this substitution results in defects in ion flux compared to wild-type SLC26A4 protein (Dossena 2006a, Dossena 2006b, Yoon 2008). This variant is also listed in the ClinVar database as likely pathogenic (Variation ID: 188998). Therefore, the c.84C>A variant satisfies our criteria for classification as pathogenic.
Invitae RCV000505875 SCV000941761 pathogenic not provided 2019-09-13 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 28 of the SLC26A4 protein (p.Ser28Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed as homozygous or compound heterozygous with other SLC26A4 variants in individuals affected with Pendred syndrome (PMID: 15679828, 16570074, 24224479, 11919333). This variant has also been observed to segregate with Pendred syndrome in a family (PMID: 29739340). ClinVar contains an entry for this variant (Variation ID: 188998). Experimental studies have shown that this missense change alters chloride uptake as well as chloride and iodide transport of the SLC26A4 protein (PMID: 18310264, 16791000). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo RCV001580204 SCV001809838 pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct criteria provided, single submitter research

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